Rheumatoid arthritis is the best known form of arthritic disease, affecting millions of patients worldwide. It is characterized by a progressive inflammation of joints and internal organs by immunocompetent cells and destruction of articular cartilage resulting in progressive morbidity and death. Prostaglandins and related eicosanoids are thought to be important mediators of these immune and inflammatory responses. Increased quantities of eicosanoids are produced by rheumatoid synovium in both organ and cell culture and are found in elevated levels in rheumatoid synovial fluid and from peripheral blood cells of affected patients. Clinical evidence suggests that early diagnosis and intervention with cytotoxic and immunomodulatory agents is essential to altering the course of the disease.
Phospholipase A.sub.2 (PLA.sub.2) is a lipolytic enzyme which hydrolyzes the 2-acyl fatty acid ester of glycerophospholipids, thus releasing arachidonic acid. Arachidonic acid has been shown to be converted into a number of biologically active compounds known as eicosanoids. PLA.sub.2 activity has been shown to be ubiquitous and to reside in several different gene products. Both membrane bound and soluble forms of the enzyme have been described. Extracellular secretion of soluble PLA.sub.2 was first described in 1980. Circulating PLA.sub.2 was implicated in endotoxin shock and has since been implicated in acute and chronic inflammatory reactions.
Currently rheumatoid arthritis is diagnosed on the basis of the patient's physical presentation and a limited number of laboratory tests. Most of these tests indicate a generalized inflammatory state and diagnosis is only reinforced on the basis of cumulative results. Of the laboratory tests designed to be more specific, the presence of rheumatoid factor has been shown to correlate with approximately 75% of bona-fide rheumatoid arthritis cases and attempts have been made to establish rheumatoid factor as a distinguishing criteria from other inflammatory diseases. Incorrect diagnoses of rheumatoid disease, based upon rheumatoid factor, however, do occur with hepatitis, sarcoidosis and infections, as well as other inflammatory joint diseases such as Reiters syndrome. In addition at least 5% of disease free individuals over age 65 test positive for the presence of rheumatoid factor. Further, elevated or depressed levels do not correspond well with flare-ups or remissions in rheumatoid disease. Clearly, rheumatoid factor is neither sensitive nor specific for the diagnosis or prognosis of rheumatoid arthritis and other more sensitive and specific methods for diagnosing and following the course of the disease are needed.
It is thus an object of the invention to provide such methods. It is also an object of the invention to provide test kits and reagents for diagnosing or following the course of rheumatoid arthritis in persons having the disease. It is a further object of the invention to provide nucleic acid sequences, polypeptides and antibodies useful in diagnosing or following the course of rheumatoid arthritis. It is yet another object of the invention to provide antisense oligonucleotides and other substances useful in the treatment of rheumatoid arthritis.